STAT6 gain-of-function variant exacerbates multiple allergic symptoms - 04/05/23

Doi : 10.1016/j.jaci.2022.12.802

Ichiro Takeuchi, MD ^a,^b,^{^{∗
These 2 authors contributed equally to this study.}}, Kumiko Yanagi, DDSc, PhD ^c,^{^{∗
These 2 authors contributed equally to this study.}}, Shuji Takada, PhD ^d, Toru Uchiyama, MD, PhD ^e, Arisa Igarashi, PhD ^c,^f, Kenichiro Motomura, MD, PhD ^f, Yuka Hayashi, MD ^f, Naoko Nagano, MD ^f, Ryo Matsuoka, MD ^f, Hiroki Sugiyama, MD ^f, Takako Yoshioka, MD, PhD ^g, Hirohisa Saito, MD, PhD ^f, Toshinao Kawai, MD, PhD ^e, Yumiko Miyaji, MD, PhD ^h, Yusuke Inuzuka, MD ^h, Yoichi Matsubara, MD, PhD ⁱ, Yukihiro Ohya, MD, PhD ^h, Toshiaki Shimizu, MD, PhD ^b, Kenji Matsumoto, MD, PhD ^f, Katsuhiro Arai, MD, PhD ^a,^h,^⁎ , Ichiro Nomura, MD, PhD ^h,^j , Tadashi Kaname, MD, PhD ^c , Hideaki Morita, MD, PhD ^f,^h,^⁎
^a Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan
^b Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
^c Department of Genome Medicine, National Research Institute for Child Health and Development, Tokyo, Japan
^d Department of Systems BioMedicine, National Research Institute for Child Health and Development, Tokyo, Japan
^e Division of Immunology, National Center for Child Health and Development, Tokyo, Japan
^f Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, Japan
^g Department of Pathology, National Center for Child Health and Development, Tokyo, Japan
^h Allergy Center, National Center for Child Health and Development, Tokyo, Japan
ⁱ National Research Institute for Child Health and Development, Tokyo, Japan
^j Division of Eosinophilic Gastrointestinal Disorders, National Research Institute for Child Health and Development, Tokyo, Japan

^∗∗Corresponding author: Hideaki Morita, MD, PhD, or Tadashi Kaname, MD, PhD, or Ichiro Nomura, MD, PhD, National Research Institute for Child Health and Development, Tokyo, Okura 2-10-1, Setagaya Ward, Tokyo 157-8535, Japan.National Research Institute for Child Health and DevelopmentTokyo, Okura 2-10-1Setagaya WardTokyo157-8535Japan^∗∗∗Katsuhiro Arai, MD, PhD, Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology, National Center for Child Health and Development, Okura 2-10-1, Setagaya Ward, Tokyo, 157-8535, Japan.Center for Pediatric Inflammatory Bowel DiseaseDivision of GastroenterologyNational Center for Child Health and DevelopmentOkura 2-10-1, Setagaya WardTokyo157-8535Japan

Abstract

Background

Allergic diseases were long considered to be complex multifactorial disorders. However, recent findings indicate that severe allergic inflammation can be caused by monogenic immune defects.

Objectives

We sought to clarify the molecular pathogenesis of a patient with early-onset multiple allergic diseases, a high serum IgE level, hypereosinophilia, treatment-resistant severe atopic dermatitis with increased dermal collagen fiber deposition, and eosinophilic gastrointestinal disorder with numerous polypoid nodules.

Methods

A missense variant in STAT6 was identified, and its function was examined using peripheral blood, transfected HEK293 cells, lymphoblastoid cell lines, and knock-in mice with the corresponding mutation.

Results

Whole-exome sequencing identified a de novo heterozygous missense variant in signal transducer and activator of transcription 6 (STAT6) (p.Asp419Asn). Luciferase reporter assay revealed that the transcriptional activity of this STAT6 mutant was upregulated even without IL-4 stimulation. Phosphorylation of STAT6 was not observed in either the patient’s T_H2 cells or lymphoblastoid cell lines without stimulation, whereas it was induced more strongly in both by IL-4 stimulation compared with healthy controls. STAT6 protein was present in the nuclear fraction of the lymphoblastoid cell lines of the patient even in the absence of IL-4 stimulation. The patient’s gastric mucosa showed upregulation of STAT6-, fibrosis-, and germinal center formation–related molecules. Some of the knock-in mice with the corresponding mutation spontaneously developed dermatitis with skin thickening and eosinophil infiltration. Moreover, serum IgE levels and mRNA expression of type 2 cytokines were increased in the knock-in mice—with or without development of spontaneous dermatitis—compared with the wild-type mice.

Conclusions

A novel STAT6 gain-of-function variant is a potential cause of primary atopic disorders.

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Graphical abstract

Il testo completo di questo articolo è disponibile in PDF.

Key words : STAT6, hyper-IgE syndrome, hypereosinophilia, primary atopic disorders, atopic dermatitis, eosinophilic gastrointestinal disorder

Abbreviations used : EGID, EoG, GOF, LCL, PAD, STAT6, WT

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Introduction

Results and discussion

	This study was supported in part by Initiative on Rare and Undiagnosed Diseases (grant nos. 19ek0109301s and 20ek0109301h) from the Japanese Agency for Medical Research and Development (AMED); National Grants-in-Aid to the National Center for Child Health and Development (grant nos. 2019A-3 [to K.A.], 2020B-10 [to I.T.], 2020B-2 [to K.M.], #29-2 [to H.M.], and 2022B-11 [to H.M.]); a Health, Labor and Welfare Sciences Research Grant for Research on Policy Planning and Evaluation for Rare and Intractable Diseases, from the Ministry of Health, Labor and Welfare (grant no. 20FC1016 [to I.N.]); and a Health, Labor and Welfare Sciences Research Grant (grant no. 21FE2001 [to H.M.]).
	Data availability: The data sets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
	Ethical considerations: This report was approved by the Institutional Review Board of the National Center for Child Health and Development, Tokyo, Japan (#378, #725, #926). Written informed consent from the patient’s parents and assent from the patient were obtained when appropriate. All animal protocols were approved by the Animal Care and Use Committee of the National Research Institute for Child Health and Development, Tokyo, Japan (#A2017-006-C03). Recombinant DNA experiments were conducted in accordance with the approved protocol (#17-3).
	Disclosure of potential conflict of interest: H. Morita has received a research grant from GlaxoSmithKline. The rest of the authors declare that they have no relevant conflicts of interest.

Esportazione

Vol 151 - N° 5

P. 1402 - Maggio 2023 Ritorno al numero

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STAT6 gain-of-function variant exacerbates multiple allergic symptoms - 04/05/23

Abstract

Background

Objectives

Methods

Results

Conclusions

Graphical abstract

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